Anti hypertensive compositions comprising 2-methyl-5, 8-dimethoxychromone and acetamides



United States Patent Office 2,9lA03 Patented Oct. 27, 1959 ANTIHYPERTENSIVE COMPOSITIONS COMPRIS- ING 2 METHYL 5,8 DIMETHOXYCHROMONEAND ACETAMIDES No Drawing. Application January 30, 1956 Serial No.562,018

8 Claims. (Cl. 167-65) This invention relates to and has for its objectthe provision of novel compositions (and methods for their preparation)useful as medicinals especially in the treatment of hypertension. Thecompositions of the invention comprise combinations of2-methyl-5,8-dimethoxychromone with certain acetamides.

Although 2-methyl-5,8-dimethoxychromone is known to be useful in thetreatment of hypertension, it has now been found that its eifect may bepotentiated by administration in association with acetamides. Thus, useof the combination of chromone and acetamide extends the duration ofaction of the chromone. Consequently, fewer doses and a smaller dailyoverall dose of the chromone is required. Furthermore, even in oraladministration, the maximum blood pressure drop is reached in anappreciably shorter time with the combination than when the chromone isgiven alone.

The acetamides useful in the combinations of this invention may berepresented by the general formula t CHCHC ON 398,428, filed December15, 1953, and now abandoned.

Particularly effective \for use in the invention are or allyl atbenzylacetamide, 0c allyl u 1 phenylethylacetamide, N,N diallyl or allyl0c benzylacetamide, and N,N-diethyl-a-allylx-benzylacetamide, especiallya-allyl-u-benzylacetamide. Also useful in the invention are any of theother compounds disclosed in the above-mentioned US. application SerialNo. 398,428. The 2-methyl-5,8-dimethoxychromone may be prepared, forexample, by contacting 2,5-dimethoxy-6-hydroxyacetophenone with ethylacetate in the presence of an alkali metal condensing agent, dehydratingthe 2,5-di methoxy-6-hydroxybenzoylacetone thereby obtained by contactwith a mineral acid, and recovering the desired chromone. Thecompositions of the invention may be prepared in any of the variousdosage-unit forms for either oral use or intravenous injection. Thus,tablets may be prepared to preferably contain about 2-10 mg. chromoneand about -250 mg. acetamide. This mixture of active ingredients may becompounded in the usual manner to contain fillers and/or binders such asstarch, dextrose, stearates, carbonates, kaolin or talc, then compressedto form the tablets. Also the mixture of active ingredients, incombination with other filling materials, if desirable, many beencapsulated for ingestion.using one or two piece gelatin capsules.Furthermore, the combination may be dissolved or suspended in an inertsolvent or solvent mixture and administered as such.

As has been indicated above it is possible to administer thecombinations of this invention by administering the componentsseparately, for example, by first administering the chromone, then theacetamide or vice-versa. Utili zing such procedure the potentiatingeffect of the acetamide on the chromone is clearly observed. However, itis simpler to utilize the combination simultaneously, since this methodis most economical and expedient. The required daily dosage of theingredients is of the order of mg. 'of acetamide and 25 mg. of chromone.However, larger or smaller quantities may be desirably used.For'exarriple, one may use as much as 1000 mg. or more of acetamide and250 mg. or more of the chromone, or as little as 25 mg. or less of theacetamide and 5 mg. or less of the chromone.

Numerous test data have been obtained showing the in vivo effectivenessof the combinations of the invention and typical results are tabulatedbelow:

EXPERIMENT A (1) l0 mg./K. chromone I.V. Drop of 50 mm.-20 minuteduration.-Total recovery in 100 minutes.

.(2) Acetamide 200 mg./K. orallytno eiiect, but

,(3) followed by 10 rug/K. chromone I.V.Drop of 50 mm.duration over 2hours To these figures it might be well to add the results on oraladministration which were supplied.

EXPERIMENT B (1) Chromone 50 mg./K. orally40% drop reached in 60minutes. Recovery complete in minutes.

,(2) Acetamide 200 mg./ K. orally no efliect, but

(3) Acetamide 200 mg./ K. orally-l-chrornone 50 mg./ K. orally45% dropreached in 30 minutes. Recovery beginning in 60 minutes-requires 120minutes for com pletion.

Following are typical formulations coming within the scope of theinvention. It is to be specifically understood, however, that theseexamples are merely illustrative andnot limitative of the invention.

Example 1.Suspensi0n (Containing u-allyl-a-benzylacetamide, 100 mg. and2- methyl-S,8-dimethoxychromone, 400mg. per 15 ml. suspension.)

a-Allyl-wbenzylacetamide "gm..- 4.0 2-methyl-5,8-dimethoxychromone gm16.0 Veegum gel -t gm. 150.0 Tragacanth gm .6 Glycerin ml 60.0 Butylp-hydroxybenzoate (.1% aqueous solution) gm .6 Propyl p-hydroxybenzoate(.1% aqueous solution) gm .6 Methyl p-hydroxybenzoate (.1% aqueoussolution) gm .6 d-Sorbitol (70% aqueous solution) ml 600.0

1) Dissolve butyl, methyl and propyl p-hydroxybenzoates in glycerin withheat.

(2) Add an equal amount of d-sorbitol.

(3) Gradually triturate tragacanth, 2-.methyl-5,8-dimethoxychromone anda-allyl-a-benzylacetamide in the mm.

(4) Add Veegum gel with constant stirring; bring to volume withd-sorbitol homogenize.

Example 2.Capsules (Containing a-allyl-a-benzylacetamide 100 mg., 2-methyl-S,8-dimethoxychron1one 400 mg.)

a-Ally-a-benzylacetamide gm 50.0 2-methyl-5,8-dimethoxychromone gm 200.0

( 1) Mix, sieve through No. 40 U.S. standard sieve. (2) Fill .5 gm. inhard gelatin capsules.

Example 3.Compressed Tablet (Containing a-allyl-a-benzylacetamide 100mg. and 2- methyl-5,S-dimethoxychromone 400 mg. per tablet.)

(1) Mix ingredients above, sieve through No. 40 U.S. standard sieve.

(2) Granulate with equal parts mucilage acacia, simple syrup.

(3) U.S.P. and distilled water.

(4) Sieve through No. 12 U.S. standard sieve.

(5) Dry at 95 F.

(6) Sieve through No. 12 U.S. standard sieve.

(7) Add talc 2% containing magnesium stearate /z%.

(8) Compress.

(9) Assay.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A pharmaceutical composition essentially containing2-methyl-5,8-dimethoxychromone; and an acetamide of the formula:

wherein X is a member of the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy; R is a member of the group consisting ofhydrogen and lower alkyl; R is a member of the group consisting of loweralkyl and allyl; and R" and R'" are each members of the group consistingof hydrogen, lower alkyl and allyl.

2. The composition of claim 1 wherein the acetamide isa-allyl-u-l-phenylethylacetamide.

3. The composition of claim 1 wherein the acetamide isN,N-diallylalkylbenzylacetamide, the alkyl compound of which is a loweralkyl.

4. The composition of claim 1 wherein the acetamide isN,N-diethy1-ot-allyl-a-benzylacetamide.

5. The composition of claim 1 wherein the acetamide isa-allyl-a-benzylacetamide,

6. A method for reducing blood pressure which comprises sequentiallyadministering (1) 2-methyl-5,8-dimethoxychromone; and (2) an acetamideof the formula wherein R is a member of the group consisting of hydrogenand lower alkyl; R is a member of the group consisting of lower alkyl;and R" and R are each members of the group consisting of hydrogen, loweralkyl and allyl.

7. A pharmaceutical composition essentially containing2-methyl-5,8-dimeth0xychromone; and an acetamide of the formula:

I CHCHCON wherein X is a member of the group consisting of hydrogen,halogen, lower alkyl and lower alkoxy; R is a member of the groupconsisting of hydrogen and lower alkyl; R is a member of the groupconsisting of lower alkyl and allyl; and R" and R are each members ofthe group consisting of hydrogen, lower alkyl and allyl in a solidpharmaceutical carrier.

8. A pharmaceutical composition essentially containing2-methyl-5,8-methoxychrornone; and an acetamide of the formula:

R R E7HOHCON/ X Bl! RIII wherein X is a member of the group consistingof hydrogen, halogen, lower alkyl and lower alkoxy; R is a member of thegroup consisting of hydrogen and lower alkyl; R is a member of the groupconsisting of lower alkyl and ally]; and R" and R are each members ofthe group consisting of hydrogen, lower alkyl and allyl in a liquidpharmaceutical carrier.

mycetin preparations, contg. acetamide, N,N-dimethyl,"

1. A PHARMACEUTICAL COMPOSITION ESSENTIALLY CONTAINING2-METHYL-5,8-DIMETHOXYCHROMONE; AND AN ACETAMIDE OF THE FORMULA: